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p53 Tumor Suppressor Gene Therapy for Cancer
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p53 Tumor Suppressor Gene Therapy for Cancer
Review Article [1] | October 01, 1999
By Jack A. Roth, MD, FACS [2], Stephen G. Swisher, MD [3], and Raymond E. Meyn, PhD [4]
Gene therapy has the potential to provide cancer treatments based on novel mechanisms of action
with potentially low toxicities. This therapy may provide more effective control of locoregional
recurrence in diseases like non–small-cell lung cancer (NSCLC) as well as systemic control of
micrometastases. Despite current limitations, retroviral and adenoviral vectors can, in certain
circumstances, provide an effective means of delivering therapeutic genes to tumor cells. Although
multiple genes are involved in carcinogenesis, mutations of the p53 gene are the most frequent
abnormality identified in human tumors. Preclinical studies both in vitro and in vivo have shown that
restoring p53 function can induce apoptosis in cancer cells. High levels of p53 expression and
DNA-damaging agents like cisplatin (Platinol) and ionizing radiation work synergistically to induce
apoptosis in cancer cells. Phase I clinical trials now show that p53 gene replacement therapy using
both retroviral and adenoviral vectors is feasible and safe. In addition, p53 gene replacement
therapy induces tumor regression in patients with advanced NSCLC and in those with recurrent head
and neck cancer. This article describes various gene therapy strategies under investigation, reviews
preclinical data that provide a rationale for the gene replacement approach, and discusses the
clinical trial data available to date. [ ONCOLOGY 13(Suppl 5):148-154, 1999]
Introduction
he concept of gene therapy to treat human disease originally developed as a potential treatment for
inherited monogenic disorders.[1,2] In theory, a disease caused by the absence or mutation of a
single gene, such as cystic fibrosis or Gaucher’s disease, could be treated and potentially cured by
inserting a normal copy of the mutant or deleted gene into a renewable population of host cells, such
as bone marrow stem cells. While conceptually simple, this strategy of gene replacement therapy is
proving to have practical complexities that make its clinical implementation more difficult than had
been anticipated. Currently available vectors have been unable to sustain high enough levels of
gene expression over long enough periods of time.
T
A major focus in gene therapy has been the treatment of cancer. Approaches have included
transferring cytokine genes to stimulate an antitumor immune response, delivering genes that
express prodrugs to tumors, and transferring genes to protect stem cells during high-dose
chemotherapy. This review will focus on restoring the function of tumor suppressor genes. In the
context of cancer, transient gene expression that triggers cancer cell death may be enough to
mediate a therapeutic effect. Expression of the transgene in only a fraction of tumor cells also may
not be limiting because these cells may alter the growth of adjacent cells.[3]
Genetic Basis of Carcinogenesis
The gene families implicated in carcinogenesis include dominant oncogenes like ras and tumor
suppressor genes like p53.[4-6] Proto-oncogenes (normal counterparts of oncogenes) ordinarily
participate in such functions as signal transduction (relaying information from the outer cell
membrane to the nucleus) and gene transcription. An abnormality (point mutation, amplification,
translocation, or rearrangement) in only one of the two alleles of a proto-oncogene is sufficient to
convert it into an active oncogene, that is, to dysregulate its function and lead to malignant
transformation.
In contrast, a single normal tumor suppressor gene in a cell is typically sufficient to perform the
normal function of the gene, but loss of function of both alleles, by mutation or deletion or a
combination thereof, leads to dysregulation of cellular growth. In addition, some tumor suppressor
gene mutations—for example, some p53 mutations—act in a “dominant negative” manner, that is, a
mutation in one allele can lead to production of a mutant p53 protein that binds to, and thereby
inactivates, the structurally normal protein encoded by the opposite allele. Viral proteins also may
bind and functionally inactivate p53.[7]
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Rationale for Restoring p53 Function in the Cancer Cell
All cancers are thought to contain multiple abnormalities in a variety of genes that control various
aspects of cell growth and development. Thus, correcting all the genetic abnormalities in the cancer
cell might seem necessary to reverse the malignant process. Correction of all genetic abnormalities
would be an impossible task, however, particularly since some of these abnormalities have not yet
been identified. Moreover, individual patterns of expression would need to be assessed—for each
gene in every patient. Fortunately, correcting a single genetic abnormality is enough in some cases
to induce tumor cell death by apoptosis.[8-10]
A number of in vitro studies that used cultured cancer cell lines demonstrated that eliminating the
expression of a single dominant oncogene (ras) or adding a normal copy of a tumor suppressor gene
(p53 or the retinoblastoma [Rb] gene) to cells that had deleted or mutated copies of these genes
reduced or even abolished critical aspects of the malignant phenotype, such as tumorigenicity in
animals or anchorage-independent growth.[10-12] Because of this, the problem of simultaneously
correcting multiple functional genetic defects in the cancer cell did not appear as daunting.
Restoring normal gene function to every cancer cell, which is beyond the capabilities of the vectors
currently available for use in gene therapy, was also thought to be necessary at one time. However,
transduced cells expressing a toxic transgene are now recognized to alter the growth of adjacent
nontransduced cells. This has been termed the bystander effect.[3]
While multiple genes offer potential targets for gene therapy in several common malignancies, our
group has focused on the goal of replacing normal p53 function. Many of the identified tumor
suppressor genes and proto-oncogenes encode proteins that are components of a network that
converges on the protein encoded by the Rb gene.[13,14] Phosphorylation of the Rb protein
increases transcription of other genes and protein synthesis, leading to cell growth. Phosphorylation
of Rb is controlled by a multimolecular complex of proteins, containing cyclins and cyclin-dependent
kinases as well as a potent inhibitor of most cyclin-dependent kinases, termed p21.[15,16] In turn,
one of the many functions of the p53 protein is regulating p21 function.[17,18] Thus, p53 plays a
central role in regulating the cell cycle because it indirectly regulates the function of Rb. When p53
function is normal, this pathway is tightly regulated; however, when p53 mutates or is absent,
uncontrolled cell growth reflects lost control of the pathway.
Moreover, p53 plays a central role in other metabolic pathways, including, importantly, control of
apoptosis.[19] In response to various toxic insults to cells, such as exposure to ionizing radiation or
chemotherapy, normal cells either pause in their cell cycle long enough to repair DNA damage or, in
other cases, undergo apoptosis; repair and programmed cell death both prevent the damaged DNA
from being passed along to the cell’s progeny. When normal p53 function is absent, however,
damaged DNA is much more likely to be passed along.[20]
Selecting the Tumor Model
Non–small-cell lung cancer is a logical target for novel therapeutic strategies for several reasons. It is
the leading cause of cancer death in the United States, and the median survival of patients who
present with stage III or IV disease, as the majority of patients do, is measured in months. For most
patients who are not potentially curable by surgery, other standard therapies are relatively
ineffective. Radiotherapy, which offers the best chance for locoregional control of disease in patients
with surgically unresectable disease, is successful in only 20% of cases, and local primary failure or
recurrence may be the only site of failure in up to one third of patients.[21]
Mutation or inactivation of p53 occurs in a high proportion of nearly all common human cancers,
including non–small-cell lung cancer.[21-23] In view of the key role of p53 in cell-cycle regulation
and apoptosis and the role of defective p53 function in carcinogenesis, attempting to replace p53
represents a logical gene replacement strategy. My colleagues and I have therefore studied this
approach in patients with non–small-cell lung cancer. Our initial approach has been based on
injecting the primary tumor with a vector expressing wild-type p53, with the aim of improving the
locoregional control of non–small-cell lung cancer.
Selecting an Efficient Vector
Most available vectors were inefficient in transducing genes into cancer cells. Thus, the next
experimental goal was to develop an efficient vector to deliver a therapeutic gene into cancer cells.
Studies of models of human tumors in vitro and in nude (immunoincompetent) mice showed that
uptake of retroviral vectors that contained wild-type p53 or antisense ras were efficient enough to
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mediate a therapeutic effect. In contrast, control vectors carrying cancer-associated p53 mutations
did not suppress cell growth, indicating that the therapeutic effect was a direct result of normal p53
expression and not a nonspecific effect caused by transduction of the vector or the p53
sequences.[24]
These experiments and many other early studies, including our first clinical trial of p53 gene
replacement therapy, used a retroviral vector that contained wild-type p53 cDNA linked to a b-actin
promoter. While retroviral vectors yield levels of gene expression sufficient to demonstrate a biologic
effect, vectors derived from adenoviruses can achieve much higher levels of gene expression, which
should offer greater therapeutic potential. Further, adenovirus vectors have the advantage of
infecting both dividing and nondividing cells, in contrast to retroviral vectors, which infect only
actively dividing cells. Adenovirus vectors do not integrate into the genome, so expression is
transient. This is not necessarily a disadvantage in cancer patients, however, since prolonged
expression is not required or even necessarily desirable after the tumor cell kill.
Given these theoretic advantages of adenoviral vectors, we selected first-generation adenoviruses in
which nonessential genes were deleted and replaced with wild-type p53 driven by a cytomegalovirus
promoter (ie, adenovirus p53 [Ad-p53]). In animal studies, subsequent treatment with Ad-p53 greatly
inhibited the tumorigenicity of intratracheally inoculated lung cancer cells.[25]
Preclinical Studies of p53 Gene Therapy
The demonstration of an antitumor effect for normal p53 transduced into cancer cells growing in
culture notwithstanding, we were concerned that only a fraction of tumor cells would be transduced
in vivo, limiting therapeutic efficacy. Thus, the discovery that viral vectors can readily penetrate
3-dimensional cancer cell matrices, indicating that they would spread beyond the site of intratumoral
injection, was encouraging.[26] Furthermore, adenovirus that contains wild-type p53 is not toxic to
normal bronchial epithelial cells in culture, and it is minimally toxic in mice, even at very high levels,
suggesting a very favorable safety profile for clinical trials.[27] In addition to the work reported with
non–small-cell lung cancer, studies in nude mouse models of squamous cell carcinoma of the head
and neck have demonstrated a significant therapeutic effect for adenovirus p53, confirming
induction of significant apoptosis.[28]
Despite the high efficiency of the cancer cell transduction achieved by viral vectors and the spread
of injected vectors beyond the site of intratumoral injection, it is unlikely that every tumor cell will be
transduced. In vivo studies of intratumoral injections of Ad-p53 into subcutaneous tumors in mice
showed a degree of regression exceeding that predicted by the transduction efficiency of the vector,
suggesting bystander effects. This phenomenon, which is critical to achieving a widespread
antitumor effect, was first noted in vivo in brain tumor cells transduced with the herpes simplex
thymidine kinase gene and then exposed to ganciclovir (Cytovene). The ganciclovir is nontoxic to
normal cells, but the transduced viral thymidine kinase converts the drug into cytotoxic ganciclovir
triphosphates, leading to the death of the transduced tumor cells.[3]
In contemplating gene replacement therapy with p53 or other tumor suppressor genes,
demonstrating that a bystander effect similar to that seen with the thymidine kinase gene also
occurred in the case of p53, was essential. Using in vivo mixing experiments, investigators
demonstrated that retroviral wild-type p53-transduced cells could reduce the growth rate of
nontransduced human lung cancer cells, indicating an operative bystander effect in this system.[29]
Several mechanisms may mediate bystander effects, which may differ depending on the gene
transduced and the specific type of tumor cell. These mechanisms include transfer of toxic metabolic
products through gap junctions, phagocytosis of apoptotic vesicles of dead tumor cells by live tumor
cells that mediate apoptosis, induction of an immune response against the tumor, and inhibition of
angiogenesis.
The so-called death receptor, Fas, also might mediate a bystander antitumor effect following
transduction of a p53 expression vector. For example, H358 lung cancer cells express abundant Fas
ligand but not the Fas protein needed for apoptosis. Wild-type p53 upregulates expression of Fas
protein by these cells, and because the protein is released in soluble form, it may traffic to other
cells, leading to a bystander effect.[30]
Expression of the wild-type p53 gene also may downregulate the expression of vascular endothelial
growth factor, which is one of the most common factors stimulating angiogenesis in human cancers.
This downregulation reduces the formation of blood vessels by tumor cells, thereby possibly
inhibiting the continued growth of the cancer.
In another study, the growth of lung cancer was studied using an orthotopic experimental model in
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which human lung cancer cells grew as xenograft tumors in nu/nu mice. Directly administering a
retroviral wild-type p53 expression vector into the tumor cells in vivo suppressed tumor growth.[31]
Subsequently, we used an adenovirus expression vector to deliver wild-type human p53 cDNA to
tumor cells. This p53 expression vector induced apoptosis in cancer cells carrying a mutated or
deleted p53, but had little effect on the growth of cells containing wild-type p53. Similar
p53-adenovirus vector constructs also inhibited growth of rat gliomas, human head and neck
cancers, and human colon cancers in nude mice and can mediate p53 gene expression in bladder
and liver cancers.[32] The products of other tumor suppressor genes, such as p16 and a truncated
Rb gene also have been found to suppress tumor growth in animal models.[32]
Synergistic Effect of Transduced p53 With Other Therapies
In addition to the antitumor effect of transduced tumor suppressor genes used as single modalities in
various experimental systems, preclinical studies demonstrated synergy between p53 replacement
therapy and DNA-damaging chemotherapeutic agents that are useful against non–small-cell lung
cancer, such as cisplatin and etoposide (VePesid).[33] Chemotherapy enhances expression of
transduced genes, whether viral or nonviral vectors are used, with a range of promoters. In one
model, adding cisplatin before p53 transfection increased apoptosis and suppression of tumor
growth.[34] The mechanism underlying this effect is not yet known. Preclinical studies also have
indicated that gene therapy may increase sensitivity to radiation.
We tested whether adenoviral-mediated wild-type p53 gene expression sensitizes colorectal cancer
cells to ionizing radiation.[35] Wild-type p53 gene transfer into the SW620 colorectal carcinoma cell
line was performed using Ad-p53 to evaluate the effect of wild-type p53 expression on radiation
sensitivity. Based on the fact that survival at 2 Gy was reduced from 55% to 23% (Figure 1), the
results indicated that this vector sensitized the cells. Flow cytometric analysis of terminal
deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-labeled cells and
in situ TUNEL staining of xenograft tumors demonstrated an increase in labeled cells after the
combination treatment. Compared with p53 gene therapy alone, this combination strategy
significantly enhanced the suppression of tumor growth in an animal model of subcutaneous tumor.
The delay in regrowth to control tumor size of 1,000 mm³ was 2 days for 5 Gy, 15 days for Ad-p53,
and 37 days for Ad-p53 plus 5 Gy, indicating synergistic interactions. These data indicate that the
delivery of wild-type p53 to cells with p53 mutations increases their radiation-sensitivity and that this
delivery may be accomplished by adenoviral-mediated gene therapy.
Additional experiments were conducted to ascertain whether the Ad-p53 vector also would sensitize
non–small-cell lung cancer cells to radiation. Two different non–small-cell lung cancer lines were
examined, H358 and H1299. Both of these cell lines have homozygous deletions of the p53 gene.
The H358 line was examined in vitro. In this case, the cells growing in culture were infected with
Ad-p53 at a multiplicity of infection (number of infectious viral particles per tumor cell) of 70 and the
cells were irradiated 48 hours following infection. Sensitization was assessed using an in vitro
clonogenic assay. Survival at 2 Gy was reduced from 70% for the cells receiving 2 Gy alone to 50%
for the cells receiving both treatments. The H1299 cells were injected into the hind legs of nude
mice. When the tumors reached 6 to 8 mm in diameter, they were injected with 1.5 × 1010 viral
particles. Two days later, the xenograft tumors were given a single radiation dose of 5 Gy. Similar to
the results with the colorectal xenografts, the non–small-cell lung cancer xenograft tumors had a
dramatic response to the combined treatment (Figure 2). The delay in regrowth to a control tumor
size of 1,000 mm³ was 1 day for the 5-Gy dose alone, 14 days for the Ad-p53 alone, and 36 days for
the combination of Ad-p53 plus 5-Gy treatments. Thus, the results for the combination of virus and
radiation appeared to indicate a synergistic interaction and validate the use of this gene therapy
strategy to treat non–small-cell lung cancer.
Based on the results of recently completed preclinical studies, Ad-p53 in combination with radiation
also may be a useful strategy for treating brain tumors. To determine the effects of
adenovirus-mediated delivery of wild-type p53 on the radioresponse of glioma tumor cells, in vitro
experiments were performed.[36] The responses of two human glioma cell lines were compared:
U87MG, which has wild-type p53, and U251MG, which has a mutant p53 allele. Monolayer cultures of
these cell lines were infected with Ad-p53, control vector dl312 or culture medium. The cultures were
irradiated 2 days later and colony formation efficiency determined.
Transfection with p53 had only a minor effect on the plating efficiency of unirradiated U87MG cells
but significantly enhanced the radiosensitivity of these cells. The surviving fraction at 2 Gy was
reduced from 0.61 in controls to 0.38 in p53-transfected U87MG cells (Figure 3). The control vector,
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dl312, did not influence radiosensitivity. The Ad-p53 vector was toxic to the U251MG cell line and,
therefore, its influence on radiosensitivity could not be determined. A flow cytometric analysis of
TUNEL-stained cells demonstrated that the Ad-p53 vector sensitized the U87MG cells to
radiation-induced apoptosis; the percentage of TUNEL-positive cells was increased following 9 Gy
from about 3% in the controls to 19% in the Ad-p53 plus 9-Gy–treated cells. These data suggest that
adenovirus-mediated p53 may enhance the radioresponse of brain tumor cells with wild-type p53
and that this radiosensitization may at least partially involve a restoration of the propensity for
apoptosis. Additional support for this concept is derived from a study showing that radiation
improves immediate transduction efficiency and duration of transgene expression from an
adenoviral vector.[37]
Clinical Studies
In our initial human study, nine patients with non-small-cell lung cancer received a retroviral vector
containing the wild-type p53 gene under the control of a b-actin promoter.[38] Other treatments had
failed in these patients, all of whose tumors had been documented as having a p53 mutation. Since
transduction via retrovirus was known to yield low titers of the transduced gene, the vector was
injected into the tumor on 5 consecutive days, using either a bronchoscope or, in the case of chest
wall lesions, a percutaneous needle.
Regression of the injected lesion was observed in three patients, while disease stabilized in three
others. One patient who died of a progressive kidney metastasis showed no evidence of viable tumor
at the treated site at autopsy 4 months following the injection. One patient’s primary disease
progressed, and two patients were inevaluable (one could not tolerate the general anesthesia and so
did not complete treatment, and the other died within 3 weeks of treatment). Polymerase chain
reaction (PCR) and/or in situ hybridization studies of posttreatment biopsies from eight patients
before treatment effects were evaluated showed that tumor cells had indeed integrated vector DNA
sequences in up to 20% of cells in certain areas of the tumors. An important finding was that TUNEL
staining (which detects DNA nicking) of the posttreatment biopsy samples showed that apoptosis
had increased following treatment compared with the pretreatment baseline.
No side effects attributable to the p53-vector sequences occurred in any patient, although
bronchoscopy-related complications occurred in three patients. We found no evidence of retroviral
sequences in DNA extracted from lymphocytes, sputum samples, or various nontumor tissues
obtained at autopsy on three patients. These results confirmed a high safety profile, successful
delivery of normal p53 sequences to tumor cells, and a biologic effect of the transduced gene.
These promising results have been supported by a more recent two-arm study in which a wild-type
p53 gene was given to 52 patients with non–small-cell lung cancer using an adenovirus vector.
Patients received Ad-p53 either alone or preceded by cisplatin, 80 mg/m² over 2 hours, 3 days before
p53 injection (cisplatin was chosen because of preclinical evidence of a synergistic effect with p53
gene replacement). A single intratumoral injection of p53 was given, either bronchoscopically or
guided by computed tomography, once per month for up to 6 months. Most patients had received
previous chemotherapy, in some cases with cisplatin, and all had tumor progression during
conventional therapy before entry into the study.
As with the study using the retroviral vector, both clinical and laboratory evidence of p53 expression
were seen. Ad-p53 alone (26 evaluable patients) mediated two partial responses and stabilized
disease in 16 patients. A higher dose of Ad-p53 increased progression-free survival. Ad-p53 plus
cisplatin (23 evaluable patients) mediated a partial response in two patients who had been treated
with cisplatin previously. One additional patient achieved a partial response but did not have the
required follow-up documentation to confirm the response. Ad-p53 plus cisplatin prolonged
progression-free survival compared with Ad-p53 alone. A majority of patients also had evidence of
vector DNA by PCR of posttreatment biopsies. Although antiadenovirus antibodies were detected in
all patients after one treatment, no anaphylaxis or other toxicities except transient fever
accompanied subsequent treatments. Perhaps surprisingly, despite high levels of serum
antiadenovirus antibody, p53 transgene expression occurred in the tumor cells, and clinical
responses were maintained.
Although these studies corrected only one of the many genetic abnormalities present in
non–small-cell lung cancer, evidence suggests an antitumor effect based directly on p53-mediated
apoptosis, as shown in the retroviral p53 trial. The two trials provided no evidence for the contrary
view that tumor stabilization and regression resulted from a nonspecific immune reaction. In the
Ad-p53 study, PCR detected vector DNA in the majority of patients, but fewer patients showed
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evidence of gene expression. Detection of gene expression following transfer of wild-type p53 in vivo
is difficult because successful transfer and expression of wild-type p53 in a tumor may destroy
evidence of gene expression if apoptosis is induced and the cells die. However, in those patients
whose serial gene expression could be quantitated by immunohistochemistry, it was clear that
expression of the transgene occurred despite the presence of high titers of antiadenovirus antibody.
It is possible that serum antibodies have little effect due to poor penetration of solid tumors as a
result of high interstitial fluid pressure. Whether suppressing the antiadenovirus immune response
would further enhance levels of transgene expression in the tumor is not known. In any case,
repeated intratumoral injections of adenoviral p53 appear safe despite increases in antiadenovirus
antibodies.
A similar strategy has been reported for treating recurrent head and neck squamous cell
carcinomas.[39] Head and neck cancer patients may benefit from improved local control, as the
principal cause of death for these patients is locoregional recurrence. In a phase I dose-escalation
study, 33 patients were injected with doses of up to 1011 plaque-forming units. Dose-limiting toxicity
or serious adverse events were not observed. Gene expression in tumor tissue was documented.
Two of the 17 patients who had unresectable disease had a partial response and six had stable
disease for up to 3.5 months. One of the patients with resectable disease was noted to have a
pathologic complete response at the time of resection. Infectious Ad-p53 was detected in sputum
and urine at the highest doses of 1011 infectious particles. Interestingly, the excretion time course
did not change in duration or amount with subsequent injections despite the presence of high titers
of antiadenovirus antibody. This raises the intriguing possibility that the antibody may not limit the
bioavailability of systemically administered Ad-p53.
Future Research and Conclusions
The first patient treated with retroviral p53 received general anesthesia, but outpatient treatment is
now given using only topical anesthesia. Injection takes about 20 minutes. The simplicity of the
treatment procedure suggests that gene transfer using Ad-p53 may provide highly cost-effective
therapy. Given the promising results of these phase I studies, phase II trials in patients with
non–small-cell lung cancer or head and neck cancer are now in progress, and plans also are under
way to expand these studies to include patients with locally recurrent breast, bladder, and ovarian
tumors who may benefit from more aggressive treatment of locoregional disease. Based on the
promising preclinical data indicating that Ad-p53 and ionizing radiation are synergistic in causing
cancer cell apoptosis, a phase II trial has been initiated in patients with unresectable, untreated
non–small-cell lung cancer combining Ad-p53 given by intratumoral injection with external-beam
ionizing radiation therapy.
The low viral titer achieved with the retroviral p53 vector and its inhibition by circulating
complement make it unsuitable for systemic (rather than intratumoral) use. These limitations do not
apply to the adenovirus vector, but its use systemically would require enhanced transgene
expression, low vector toxicity, and, ideally, elimination of the immune response to the vector.
Modification of the vectors used may reduce expression of endogenous adenoviral proteins, leading
to a diminished anti-adenoviral immune response.[40] The addition of agents that enhance
transgene expression may increase the effectiveness of low levels of transgene expression
sufficiently to render them therapeutic.
Also useful would be a method of targeting delivery to the tumor. Early clinical work has suggested
that some systemic effect occurs from adenovirus shed from the intratumoral injection site, as
autopsy evidence has indicated that vector DNA was detected in distant tumor deposits. Other areas
of current research include methods of increasing levels of p53 expression and suppression of the
immune response via concomitant administration of low-dose etoposide.[32]
In conclusion, clinical trials have shown that repeated intratumoral administration of Ad-p53 is well
tolerated and not associated with major toxicity. Evidence supports both gene transfer and gene
expression in the majority of the tumors. Progressively growing tumors refractory to conventional
treatments have shown objective clinical responses to Ad-p53.
In the near future, potentially promising areas for gene replacement therapy include the treatment
of locally advanced disease, adjuvant and neoadjuvant treatment of patients with resectable tumors,
the use of gene therapy to sensitize tumors to radiotherapy and chemotherapy, and, potentially, the
treatment of localized premalignancy. Gene replacement therapy also may come full circle since
basic and clinical research in cancer also may help solve the obstacles that have inhibited the
application of gene therapy to monogenic inherited diseases. Given the rapid pace of recent
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progress and the explosion of interest in gene therapy, we envision that in the near future, gene
therapy will take its place alongside chemotherapy, radiotherapy, and surgery as one of the tools
routinely available to help treat patients with cancer.
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p53 Tumor Suppressor Gene Therapy for Cancer
Published on Physicians Practice (http://www.physicianspractice.com)
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[2] http://www.physicianspractice.com/authors/jack-roth-md-facs
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[4] http://www.physicianspractice.com/authors/raymond-e-meyn-phd
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